T cell receptor-engineered T cells targeting a human endogenous retrovirus in kidney cancer.
Authors: Stefan Barisic, Elizabeth M. Brahmbhatt, Elena Cherkasova, Rosa Nadal, Ujjawal Savani, Stephanie Pierre, Long Chen, Timothy T. Spear, Gina M. Scurti, Gang Zeng, Gordon Parry, David F. Stroncek, Steven L. Highfill, Annika V. Dalheim, Robert N. Reger, Michael I. Nishimura, Richard W. Childs
Journal: Journal of Clinical Oncology (2023)

4542 Background: Previously, our group described a novel human endogenous retrovirus type E (CT-RCC HERV-E) that is selectively expressed in most clear cell renal cell carcinomas (ccRCC). Here, we report the characterization and preclinical testing of a T cell receptor (HERV-E TCR) that targets an HLA-A11-restricted 10-mer peptide antigen (CT-RCC-1) that is derived from CT-RCC HERV-E. Methods: From a patient with ccRCC who had prolonged immune-mediated tumor regression following an allogeneic hematopoietic stem cell transplant, we identified a CD8 + T cell clone with HLA-A11-restricted specificity for the CT-RCC-1 peptide. The TCR of this clone was encoded into a retroviral vector containing a truncated CD34 cassette as a selection marker. Gene-engineered T cells expressing the HERV-E TCR (HERV-E T cells) were characterized for tumor recognition, lysis, and cross-reactivity. In vivo anti-tumor activity was assessed in a xeno-murine model using a human subcutaneous ccRCC tumor graft. A good manufacturing practice (GMP)-compliant method to produce HERV-E T cells was implemented for a subsequent clinical trial in humans with metastatic ccRCC. Results: When transduced into human T cells, the HERV-E TCR showed CD8-dependent specific recognition and lysis of HERV-E-expressing ccRCC cells that were HLA-A11+. The extent of tumor cytotoxicity correlated with CT-RCC HERV-E mRNA expression levels and HLA-A11 surface density (r=0.82). Cross-reactivity assessment established that there were no naturally occurring peptides with substantial sequence identity to CT-RCC-1 that could serve as alternative targets for HERV-E T cells. Further, immunopeptidomics and in silico analyses provided strong evidence that presentation of the CT-RCC-1 epitope depends exclusively on the transcription of the CT-RCC HERV-E genomic region. In a murine model, human HERV-E T cells mediated regression of established human ccRCC tumor grafts, significantly prolonging animal survival compared to controls that either received non-transduced T cells or no T cells (median survival 50 days vs. 20 and 20 days, respectively; p&lt;0.001). Finally, the GMP-compliant production of HERV-E T cells yielded pure populations (i.e., &gt;90% TCR-transduced) of HERV-E T cells that were highly cytotoxic to ccRCC tumor cells. The expansion numbers of GMP-produced cells were sufficient for testing the safety of the adoptively infused T cells in a phase I clinical trial. Conclusions: Here, we provide the first data showing T cells armed with a HERV-E TCR acquire specific anti-tumor activity in vitro and in vivo against ccRCC cells. These preclinical data provide the foundation for an ongoing first-in-human phase I clinical trial evaluating the safety of HERV-E T cell infusions in patients with advanced ccRCC.